Deposition of beta-amyloid peptides (Abeta) has been causally linked to the development of both Alzheimer's disease and the senile plaques characteristic of this disease. The development of murine models for AD by overexpression of mutant amyloid precursor protein (APP) has stimulated the search for therapeutic agents capable of intervening in this cycle of neurodegeneration. Several recent studies have demonstrated the feasibility of generating therapeutic antibodies capable of targeting Abeta plaques in these mouse models, leading to plaque reduction and accompanied improvement in age-related behavioral impairment. Previous studies from this laboratory have established the critical contribution of cellular Fc receptors for IgG in the in vivo activity of therapeutic antibodies. The present proposal is focused on a genetic approach to determining the mechanisms by which these anti-Abeta antibodies mediate their effector responses in vivo. Three specific aims are proposed. The first is to determine the antibody responses and in vivo plaque reduction after Abeta immunization of FcR-deficient mice and APP transgenic mice with or without FcR deficiency. Since different Fc receptors can either enhance or inhibit antibody responses and cellular activation responses, the relative contribution of the activating or inhibitory Fc receptors will be evaluated for efficacy in active immunization in vivo in various FcR-deficient mice and in APP transgenic mice with or without deficiency in specific FcRs. In Aim 2, the contribution of Fc- mediated effector pathways for passively administered anti-Abeta antibodies to the in vivo clearance of plaques in APP transgenic models will be evaluated. Monoclonal antibodies to fibrillar Abeta will be evaluated in APP transgenic and APP/FcR-deficient mice. Antibodies will be modified in their Fc regions to limit their binding to specific FcRs in order to evaluate their contribution cells responsible for these responses will be evaluated in Aim 3, which will attempt to identify both the effector cells and the relevant receptors on those cells that are responsible for the in vivo efficacy of passively administered antibodies. Animals either deficient in specific effector cells (macrophage, mast cell, neutrophil or NK cells) or effector cell receptors will be crossed to APP transgenic mice and studied for their ability to mediate anti-plaque activity to administered antibodies. The role of microglial cells will be evaluated in vivo by generating the appropriate conditional deletions in the cellular Fc receptors of these cells. The results of these studies will provide a mechanistic basis for engineering therapeutic antibodies in AD to optimize their effector responses, and for developing more effective immunization protocols for maximal therapeutic effects in vivo.